The proposed studies will focus on the role of the major histocompatibility complex MHC) in the spontaneous systemic autoimmune disease of mice expressing the lpr gene. We have discovered that MHC alleles modify autoimmunity in this murine model. We will take advantage of the many recombinant murine mouse strains to localize the responsible MHC gene or genes. We will utilize unique lpr recombinant mouse strains to ask whether the T-B cell collaboration underlying autoantibody production in this model is restricted by molecules of the MHC. Recent technology makes it possible to identify peptides of processed antigen associated with surface MHC molecules. We will isolate class II MHC molecules from lpr mice and determine the peptides with which they are associated. These studies are expected to yield clues to the nature of T-cell recognition of autoantigens. We will also determine the peptides which result from the processing of known autoantigens by antigen presenting cells of normal and autoimmune mice. We will construct autoantigen-presenting B lymphocytes by transfecting CH12 tumor cells with anti-Sm H and L chains, and will examine peptides bound to their surface class Il MHC molecules. The role of MHC in development of the T-cell receptor repertoire in lpr mice will be examined using class I- and class Il-deficient lpr mice. These studies are expected to elucidate the cellular mechanisms responsible for autoantibody production in this murine model.